Erectile dysfunction or impotence is characterized by the inability to achieve or maintain erection or tumescence of the penis. Impotence can be secondary to a wide variety of causes and may be physiological or psychological in origin. This condition is estimated to affect approximately 10-20 million American men chronically, but affects all men occasionally. For example, erection of the penis is inhibited in normal men due to anxiety, exertion or sexual disinterest. Sexual activity includes physical exertion and as men age, the inhibitory effects of exertion may overcome normal arousal mechanisms.
The etiology of chronic impotence may be psychogenic (32%), mixed psychogenic and organic (14%), organic (41%) or anatomical (13%). Organic causes include arterial insufficiency (27%), cavernous leakage (28%), neurological damage (13%), endocrinological defects (2.3%) and Peyronie's disease (13.1%). Govier, F. E. Timing of Penile Color Flow Duplex Ultrasonography Using a Triple Drug Mixture. J. Urol, Vol. 153(5) (May 1995), pp. 1472-1475. Thus, about 30% of all cases of impotence are primarily vascular in origin.
Compounds which produce or enhance arterial vasodilation or bring about cavernous vein constriction may be successful for the treatment of impotence. See U.S. Pat. Nos. 5,567,706 and 5,583,144 incorporated by reference. Similarly, compounds which counteract inhibitors of erection, such as catecholamines, may also contribute to effectiveness. Compounds which have been used in the pharmacological induction of erection were the vasodilator papaverine and the catecholamine antagonist, phenoxybenzamine. Such compounds may be administered by injection into the corpora cavernosa of the penis. Brindly, G. S. Cavernosal Alpha-blockage: A New Technique for Investigating and Treating Erectile Impotence, Br J. Psychiatry, Vol. 143 (1983), pp. 332. These compounds are thought to work by mimicking the physiological mechanisms that relax penile smooth muscle.
Erection of the penis may be a self-perpetuating process of three steps: 1) vasodilation; 2) release of endogenous smooth-muscle relaxants; and, 3) progression of these effects distal from the initial site of onset. This has been termed the "cascade effect". According to this hypothesis, local induction of vasodilation in the corpus cavernosum may perpetuate itself into full erection of the penis whether or not the original vasodilator diffuses throughout the tissue. Where the concentration of vasoactive drug is highest, there is a local increase in blood flow, an activation of endothelium-mediated relaxing factors such as endothelium-derived nitric oxide, and an enlarging zone of regional smooth muscle relaxation. This "cascade" of a relaxation-inflow-relaxing effect can produce an erection. Support for this hypothesis is found in the observation that high doses of vasoactive drugs are required for erection in impotent patients with endothelial cell dysfunction, such as diabetes and hypercholesterolemia, presumably due to inability of these cells to produce vasodilators. The hypothesis is also supported by the observation that injected vasoactive drugs do not appear to uniformly diffuse from the injection site throughout the corpora of the penis, but are still capable of producing a full erection.
One of the first compounds used successfully for intracavernosal treatment of impotence is papaverine hydrochloride. Papaverine is an opium alkaloid and works as a smooth muscle relaxer possibly by cyclic GMP phosphodiesterase inhibition. It relaxes the musculature of the vascular system of the penis and increases blood flow. The effectiveness of papaverine hydrochloride injection depends on the dose, but has been reported to cause penile hematoma, elevated liver enzymes, priapism and lightheadedness in some patients, particularly if over-used. The free base of papaverine has been tried as a topical agent in the treatment of erectile dysfunction. In concentrations up to 20%, it was not sufficiently effective for clinical use. Kim, E. D. Papaverine Topical Gel Treatment For Erectile Dysfunction, Urology, Vol. 133(2)(1995), pp. 361-365.
Another compound found effective in treating impotence is phentolamine hydrochloride or phentolamine methane sulfonate (phentolamine mesylate), described in U.S. Pat. No. 2,503,059 incorporated by reference. Phentolamine free base is a nonspecific alpha-adrenergic antagonist and has been successful in inducing penile erection, particularly when used in combination with papaverine. This combination was found to produce greater vasodilation of the arteries of the penis than either phentolamine or papaverine used alone.
Another compound found useful in the treatment of impotence is prostaglandin E.sub.1, a naturally occurring compound that acts to increase arterial inflow to the penis and may also restrict venous outflow. Prostaglandin E.sub.1 is preferred to other compounds used in injections for the treatment of impotence because it is metabolized locally in the penis and is less likely to cause systemic symptoms such as hypotension. Further, use of prostaglandin E.sub.1 has been found to result in a significantly lower incidence of penile hematomas from injections than either papaverine or phentolamine. However, prostaglandin E.sub.1 is considerably more expensive than other therapies and causes pain distal from the site of injection.
A synthetic form of prostaglandin E.sub.1, alprostadil USP (alprostadil), is a long-chain carboxylic acid with vasodilatory effects. Alprostadil acts to increase arterial inflow to the penis. In vitro studies have shown that alprostadil causes a dose-dependent smooth muscle relaxation in isolated corpus cavernosum and corpus spongiosum preparations. When used in vivo, it is thought that intraurethral alprostadil is absorbed from the urethra, transported throughout the erectile bodies of the penis by way of communicating vessels between the corpus spongiosum and corpus cavernosum, and induces vasodilation of the targeted vascular beds.
Various forms of alprostadil are available on the market, such as CAVERJECT (Upjohn, Kalamazoo, Mich.), which is an injectable form of alprostadil. Another form of alprostadil is MUSE (Vivus, Inc., Menlo Park, Calif.) which is a combination of alprostadil and polyethylene glycol. Intraurethral administration of MUSE has been reported to result in a substantial increase of cavernosal artery diameter and as much as a 10-fold increase in peak systolic flow velocities. Injections of alprostadil have been reported to cause pain, bleeding, hematomas and scar tissue leading to Peyronie's Disease in some patients.
Urethral inserts or suppositories have been developed as an alternative to intracavernousal injection therapy. For example, U.S. Pat. No. 5,242,391, incorporated by reference, describes a device for the urethral insertion of a pellet containing alprostadil. The device has been reported to be effective about 65% of the time in doses of 125 to 1000 micrograms of alprostadil. However, urethral inserts do not appear to be as successful in treating impotence as intracavernousal injections.
The urethra is sensitive to irritants. There have been some reports that local anesthetic agents such as procaine and lidocaine can relieve some of the irritation upon intracavernousal injection. Schouman, M., Suppression of Prostaglandin E-1 Induced Pain By Dilution of the Drug With Lidocaine Before Intracavercousal Injection, J. Urology, Vol 148 (1992), pp.1266.
Androgenic steroids may also have a role in induction of erection, especially for patients with hypogonadism. Dihydrotestosterone has been administered transdermally, but has never been administered intraurethrally. Because dihydrotestosterone is fat-soluble, this may be a reasonable route of delivery. Tostain, J., Androgen Treatment of Erectile Dysfunction: When?How? Progres en Urologie, Vol. 7 (1997), pp. 314-319.
Combinations of papaverine, phentolamine and alprostadil have been shown to be effective in treating impotence. For example, intracavernousal injections of this three-way combination, known as "tri-mix", can be more effective in treating impotence with fewer side effects than papaverine, phentolamine or alprostadil used alone. Together, these compounds appear to act synergistically to increase arterial inflow, dilate sinusoidal smooth muscles, and restrict venous outflow, all promoting erectile activity with greater success and in smaller doses than single compound therapies. An example of a dosage combination for tri-mix is 10 micrograms of alprostadil, 500 micrograms of phentolamine and 15 mg of papaverine. Dosing of tri-mix preparations has not been standardized.
Agents for the formation of cationic liposomes are known to increase the solubility of substances they contain in cell membranes. Cationic phospholipids have been described for this purpose, such as phosphatidylethanolamine and phosphatidylcholine. Medium chain fats are useful for the solubilization of chemicals in membranes because they are both fat and water soluble. Therefore, diacylphosphatidylcholine, where the acyl groups are medium chain fats, may be especially efficacious as an emulsifier to aid the uptake of organic compounds by cell membranes. Dilauroylphosphatidylcholine has been disclosed as an ingredient in a composition to form cationic liposomes, for example, in U.S. Pat. No. 5,552,157, incorporated by reference. In the invention, cationic liposomes may form spontaneously when a composition as described is mixed with moisture from the urethra.